Shell-and-core dosage form approaching zero-order drug release

ABSTRACT

Drugs are formulated as oral dosage forms for controlled release in which the release rate limiting portion is a shell surrounding the drug-containing core. The shell releases drug from the core by permitting diffusion of the drug from the core. The shell also promotes gastric retention of the dosage form by swelling upon imbibition of gastric fluid to a size that is retained in the stomach during the postprandial or fed mode.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] This invention is in the general field of pharmaceuticals, andrelates in particular to formulations for drugs that benefit from aprolonged time of controlled release in the stomach and uppergastrointestinal (GI) tract, and from an enhanced opportunity forabsorption in the stomach and upper GI tract rather than the lowerportions of the GI tract. One goal of this invention is to release drugsin a controlled manner over an extended period of time. Another goal isto extend the time of delivery into the stomach of drugs that arepreferentially absorbed high in the GI tract, and thereby to achieve agreater and more prolonged therapeutic effect with potentiallydiminished side effects. This will reduce the frequency ofadministration required and achieve a more efficient use of the drugsand a more effective treatment of local stomach disorders. A third goalis to minimize both lower-tract inactivation of the drug and drugeffects on the lower intestinal flora.

[0003] 2. Description of the Prior Art

[0004] Drugs that are administered in the form of conventional tabletsor capsules become available to body fluids at a rate that is initiallyvery high, followed by a rapid decline. For many drugs, this deliverypattern results in a transient overdose, followed by a long period ofunderdosing. This is a pattern of limited clinical usefulness. Improveddelivery patterns were first made available in the 1970's with theintroduction of a variety of controlled delivery systems. These systemslowered the amount of drug released immediately after dosing andextended the time period over which drug release continued, therebyminimizing both the overdose and the underdose effects. Theseimprovements provided effective medication with reduced side effects,and achieved these results with reduced dosing frequency.

[0005] Many of these controlled delivery systems utilize hydrophilic,polymeric matrices that provide useful levels of control to the deliveryof drugs. Such matrices do not provide adequate control over the drugrelease rate, but instead provide a release pattern that approximatessquare-root-of-time kinetics in which the total amount of drug releasedis approximately proportional to the square root of the elapsed time.With this release pattern in an aqueous medium, much of the drug in thematrix of many of these formulations is released into an aqueous mediumwithin the first hour.

[0006] The benefits of a constant release rate with regard to prolongingtherapeutic efficacy while minimizing side effects are well established.It is well known in the art that a nearly constant release rate thatsimulates zero order kinetics can be obtained by surrounding a tabletcore with a membrane or coating. The membranes or coatings described inthe art are typically 1-5% of the weight of the tablet. Unfortunately,swelling of the tablet can disrupt the membrane and change the kineticsconsiderably from zero order. U.S. Pat. No. 4,892,742, issued Jan. 9,1990 (assignee: Hoffman-La Roche Inc.; inventor: Shah) discloses atablet consisting of:

[0007] 1) a core consisting of 5-35% of a water insoluble polymer matrixand 65-95% of a water soluble active ingredient; and

[0008] 2) a membrane coating comprising 5-10% of the weight of thetablet and consisting of a rate-controlling polymer.

[0009] The preferred coating material is ethyl cellulose or aplasticized ethyl cellulose and is a typical controlled release coatingfor a tablet. The lack of swelling of these membranes and the insolublecore allow the membrane coating to remain intact throughout the releaseprocess without breakage, thereby preventing exposure of the core.Without swelling to a minimal size, neither gastric retention of thetablet nor sustained delivery of the active ingredient to the uppergastrointestinal (GI) tract would be achieved.

[0010] U.S. Pat. No. 4,629,620, issued Dec. 16, 1986 (assignee: ABFerrosan; inventor: Lindahl), describes membrane-coatedsustained-release tablets where the membrane is an insoluble polymercontaining pore-forming agents. Like the tablets and membrane coatingsof the Shah patent (no. 4,892,7⁴2), the tablets and membranes of theLindahl patent are non-swelling and are not retained in the upper GItract.

[0011] U.S. Pat. No. 5,500,227, issued Mar. 19, 1996 (assignee:Euro-Celtique, S.A.; inventor: Oshlack) discloses the use of acontrolled release tablet that consists of:

[0012] 1) an immediate release tablet core containing an insoluble drug;and

[0013] 2) a thin hydrophobic coating material.

[0014] This patent does not include any disclosure or suggestion thateither the membrane or the tablet swells, and thus the patent does notdisclose a manner of confining controlled release to the upper GI tract.

[0015] U.S. Pat. No. 4,756,911, issued Jul. 12, 1988 (assignee: E.R.Squibb & Sons, Inc.; inventor: Drost) discloses a controlled releasetablet for procainamide hydrochloride consisting of:

[0016] 1) a core containing about 70% (on a weight basis) of the drug,from 5 to 15% by weight of the hydrocolloid gelling agent,hydroxypropylmethyl cellulose, and from 0 to 8% of non-swellablebinders; and

[0017] 2) a water permeable coating film comprised of a mixture of atleast one hydrophobic and one hydrophilic polymer.

[0018] This patent teaches that the entry of water through the filmcoating causes the membrane to peel off in 2 to 4 hours after ingestionof the tablet. Drug release proceeds from the core alone.

[0019] U.S. Pat. No. 4,891,223, issued Jan. 2, 1990 (assignee: AirProducts and Chemicals, Inc.; inventor: Ambegaonkar) disclosescompositions containing:

[0020] 1) an active ingredient that is soluble in the release medium;

[0021] 2) an inner coating that is water soluble and swellable; and

[0022] 3) a second outer coating that is water insoluble.

[0023] The second outer coating is disclosed as being able to stretchsufficiently to remain in contact with the inner layer, but the secondouter coating still may limit the swelling of the composition. Theinvention described involves controlled-release beads rather thantablets and are far below the size that is necessary to confine releaseof the active ingredient to the upper GI tract.

[0024] The prior art also includes disclosures of multilayer tabletsdesigned to provide release profiles that are intermediate betweensquare-root-of time and zero-order. This prior art is listed below. Themulti-layered tablets disclosed in the these patents may swellsufficiently to allow controlled delivery to the upper GI tract, butthey do not include a swelling outer layer that fully encloses a core.The outer layers are only partial, discontinuous coatings and thus arenot subjected to the large strains that are caused by differentialswelling.

[0025] U.S. Pat. No. 5,783,212, issued Jul. 21, 1998 (assignee: TempleUniversity; inventor: Fassihi) discloses a three-layer tablet, i.e., acore with a partial coating on only two sides, described as:

[0026] 1) a drug layer consisting of a swellable, erodible polymer; and

[0027] 2) two barrier layers comprising swellable, erodible polymersthat erode and swell faster than the drug layer.

[0028] There is no disclosure or suggestion that the swelling anderosion are matched among the three layers, nor is there any recognitionthat the drug layer swells faster. There is no disclosure of a swellingmembrane or any recognition of the loss of control over the release ratecaused by a disrupted membrane.

[0029] U.S. Pat. No. 5,549,913, issued Aug. 27, 1996 (assigness: InverniDella Beffa, S.p.A.; inventor: Colombo), teaches the use of athree-layer tablet where:

[0030] 1) two external layers, each covering only one side, comprised ofhydrophilic swelling polymers and at least one of which contains drug;and

[0031] 2) an interposing layer controlling the release of the drug.

[0032] In this multilayer tablet, the drug is released not through aswelling membrane or coating, but instead through an erodible or solublelayer.

[0033] Conte et al., in Biomaterials 17(1996):889-896, disclose two- andthree-layer tablets with barrier layers that swell or erode. Thesebarrier layers are described as partial coatings and as such do not formbarriers that must remain intact under the pressure arising from coressurrounded by coatings that swell at different rates.

[0034] Published international application WO 99/47128, published Sep.23, 1999 (applicant: Bristol-Myers Squibb; inventor: Timmins) disclosesa pharmaceutical tablet consisting of:

[0035] 1) an inner phase containing drug and an extended releasematerial; and

[0036] 2) an outer phase that is continuous and comprised of an extendedrelease material;

[0037] the inner phase being dispersed throughout the outer phase. Theextended release materials described in WO 99/47128 can swellsubstantially to confine delivery to the upper GI tract. The outercontinuous phase is a dispersion and not a coating or membrane. The drugrelease profiles resulting from this invention consequently deviatesubstantially from zero-order and actually exhibit a release profilethat is proportional to the square root of time.

[0038] One method of prolonging the release of a highly water-solubledrug is disclosed in International Patent Application Publication No. WO96/26718, published Sep. 6, 1996 (applicant: Temple University;inventor: Kim). The method disclosed in WO 96/26718 is the incorporationof the drug into a polymeric matrix to form a tablet that isadministered orally. The polymer is water-swellable yet erodible ingastric fluids, and the polymer and the proportion of drug to polymerare chosen such that:

[0039] (i) the rate at which the polymer swells is equal to the rate atwhich the polymer erodes, so that the swelling of the polymer iscontinuously held in check by the erosion, and zero-order releasekinetics (constant delivery rate) of the drug from the matrix aremaintained;

[0040] (ii) the release of drug from the matrix is sustained over thefull erosion period of the polymer, the tablet therefore reachingcomplete dissolution at the same time that the last of the drug isreleased; and

[0041] (iii) release of the drug from the matrix is extended over aperiod of 24 hours.

[0042] A key disclosure in WO 96/26718 is that to achieve the release ofdrug in this manner, the polymeric matrix must be a polymer of lowmolecular weight. If, by contrast, a polymer of high molecular weight isused and the swelling rate substantially exceeds the erosion rate, thelack of erosion will prolong even further the delivery of the drugresiding close to the center of the tablet and even prevent it frombeing released. Thus, there is no disclosure in WO 96/26718 that a drugof high water solubility can be released from a high molecular weightpolymer in a period of time substantially less than 24 hours, or thatany advantage can be obtained by the use of a polymer that does noterode as quickly as it swells. This is particularly significant sinceany tablet, including swollen tablets, will pass from the stomach afterthe termination of the fed mode, which typically lasts for only 4 to 6hours. Moreover, this patent does not teach the use of a membrane orcoating, much less one that swells and stays in contact with the corethroughout the release of the drug.

[0043] In many cases, the passage of a drug from the stomach into thesmall intestine while the drug is still in a tablet or other dosage formraises problems that lower the therapeutic efficacy of the drug, due toeither the absence of the favorable conditions in the stomach, theexposure to unfavorable conditions in the colon, or both.

[0044] For example, most orally administered antibiotics are capable ofaltering the normal flora of the gastrointestinal tract, andparticularly the flora of the colon. One result of these alterations isthe overgrowth of the organism Clostridium difficile, which is a seriousadverse event since this organism releases dangerous toxins. Thesetoxins can cause pseudomembranous colitis, a condition that has beenreported as a side effect of the use of many antibiotics due to passageof the antibiotics from the stomach through the GI tract to the smallintestine. In its milder forms pseudomembranous colitis can cause mildnausea and diarrhea, while in its stronger forms it can belife-threatening or fatal. Examples of antibiotics that pose this typeof threat are amoxicillin, cefuroxime axetil, and clindamycin.Cefuroxime axetil (i.e., the axetil ester of cefuroxime), for example,becomes active when hydrolyzed to free cefuroxime, but when this occursprior to absorption, damage to essential bacterial flora can occur.Hydrolysis to the active form typically occurs in the tissues into whichthe ester has been absorbed, but if the ester reaches the lowerintestine, enzymes in the lower intestine cause the hydrolysis to occurin the intestine itself, which not only renders the drug unabsorbablebut also converts the drug to the active form where its activity altersthe flora. Further examples are clarithromycin, azithromycin,ceftazidime, ciprofloxacin, and cefaclor. A goal of the presentinvention is to avoid antibiotic-induced overgrowth of the lowerintestinal flora by administering antibiotics, regardless of their levelof solubility, in a manner that confines their delivery to the stomachand upper small intestine.

[0045] A class of drugs that suffer a loss of benefit from rapid initialrelease are those that are susceptible to degradation by exposure togastric fluid, either due to the action of gastric enzymes or as theresult of low solution pH. One example of such a drug is topiramate, adrug that is used for the treatment of epilepsy. Topiramate is absorbedmost rapidly in the upper GI tract, but when made available at thissite, it is hydrolyzed by the acidic environment of the stomach.Avoidance of this high rate of hydrolysis requires a dosage form thatdoes not expose the drug to the acidic environment for an extendedperiod.

[0046] A class of drugs that suffer a loss of benefit when allowed topass into the small intestine are those that are absorbed only in theupper GI tract and suffer from incomplete absorption or from widedifferences in absorption, both within a single patient and betweendifferent patients. One example of such a drug is cyclosporine, a drugof low solubility that is used as an immunosuppressant to reduce organrejection in transplant surgery. In addition to its low solubility,cyclosporine has a low absorption rate of about 30% on average, togetherwith wide absorption variability ranging from as little as 5% in somepatients to as much as 98% in others. The variability is attributable inpart to differences among the various disease states existing in thepatients to whom the drug is administered, and in part to differences inthe length of time between the transplant surgery and the administrationof the drug. The variability can also be attributed to the poor aqueoussolubility of the drug, variations in the gastric emptying, variationsin the length of time required for intestinal transit between thestomach and the colon, variations in mesenteric and hepatic blood flow,variations in lymph flow, variations in intestinal secretion and fluidvolume, variations in bile secretion and flow, and variations inepithelial cell turnover.

[0047] Another class of drugs that suffer a loss of benefit when allowedto pass into the small intestine are drugs that are susceptible todegradation by intestinal enzymes. The degradation occurs before thedrug can be absorbed through the intestinal wall, leaving only afraction of the administered dose available for the intended therapeuticaction. An example of such a drug is the pro-drug doxifluridine(5′-deoxy-5-fluouridine (dFUR)). The activity of this pro-drug dependson its activation to 5-fluorouracil by pyrimidine nucleosidephosphorylases. These enzymes are found in tumors as well as in normaltissues, and their activity in tumor cells is more than twice theiractivity in normal tissue. In addition, these enzymes demonstrate theirhighest activity in the large intestine. When doxifluridine isadministered orally, it risks being converted to 5-fluorouracil in theintestine before it reaches the tumors. 5-Fluorouracil is much moretoxic than doxifluridine and causes intestinal toxicity (nausea anddiarrhea) and severe damage to the intestinal villi. Other drugs thatcan produce a similar effect upon reaching the colon are cyclosporineand digoxin.

[0048] A further class of drugs whose effectiveness declines when thedrugs are allowed to pass into the large intestine are those that aresusceptible to inactivation by drug transporters that reside in lowergastrointestinal tract enterocytes. The inactivation occurs before thedrug penetrates the intestinal wall, leaving only a fraction of theadministered dose available for the intended therapeutic action. Oneexample of a drug transporter is the p-glycoprotein efflux system, inwhich a p-glycoprotein acts as an absorption barrier to certain drugsthat are substrates for the p-glycoprotein. The barrier acts byattaching to these drugs and transporting them drug back into the lumen,e.g., the duodenum, jejunum/ileum or colon, from which they wereabsorbed, or by preventing them from being absorbed at all. Thisrestriction of the drug to the interior of the GI tract is effectivelyan inactivation of the drug if the drug must pass out of the GI tractinto the bloodstream to be effective. Thus, while the p-glycoproteinefflux system is useful in many respects, such as preventing toxiccompounds from entering the brain, it interferes with the efficacy ofcertain drugs whose absorption is necessary in achieving the therapeuticeffect. The p-glycoprotein concentration is lowest in the stomach andincreases in concentration down the GI tract to the colon where thep-glycoprotein is most prevalent. These drugs therefore would benefitfrom controlled release over an extended period into the upper GI tractwhere p-glycoprotein is lowest. Cyclosporine is an example of a drug oflow solubility that is susceptible to inactivation by the p-glycoproteinefflux system, in addition to its susceptibility to degradation bycolonic bacterial enzymes. Other examples of drugs that are susceptibleto the p-glycoprotein efflux system are the anti-cancer drug paclitaxel,ciprofloxacin, and the HIV protease inhibitors saquinavir, ritonavir,and nelfinavir.

[0049] A still further class of drugs that suffer from loss ofeffectiveness when not fully absorbed before reaching the colon aredrugs that require an acidic environment for effective bioavailability.For certain drugs, the pH at a given site within the GI tract is anessential determinant of the bioavailability of the drug, since thesolubility of the drug varies with pH. The stomach has a low pH and thuscreates an acidic environment, while the small intestine has a higherpH, creating a slightly acidic to alkaline environment. Some drugsachieve bioavailability only when ionized by the acidic environment ofthe stomach. Other drugs are more bioavailable in a non-ionized state.Acidic drugs that have a low pK, for example, are in the neutral form inthe stomach, and those that are more bioavailable in this state arepreferentially absorbed in the stomach or upper duodenum. Examples ofhighly soluble drugs that meet this description are esters ofampicillin. Examples of low solubility drugs that behave similarly areiron salts, digoxin, ketoconazole, fluconazole, griseofulvin,itraconazole, and micoconazole. Iron salts are used in the treatment ofthe various forms of anemia, digoxin is used in the treatment of heartdisease, and ketoconazole is used in the treatment of systemic fungalinfections such as candidiasis, canduria, blastomycosis,coccidiomycosis, histoplasmosis, chronomycosis, and pacococcidiomycosis.Still further drugs that are more absorbable in the neutral form that ismaintained at low pH are those whose molecular structure contains atleast one group that becomes ionized in the pH range of 5 through 8,which is the pH range encountered in the small intestine and the regionof the colonic junction. In addition, zwitterionic drugs may be betterabsorbed in a charged form that is present in the acidic environment ofthe stomach or the duodenal cap. The bioavailability of all of thesedrugs can be maximized by confining them to the acidic environment ofthe stomach while controlling their release rate to achieve an extendedrelease profile.

[0050] A still further example of drugs that lose their efficacy uponreaching the lower portions of the GI tract are drugs that are solublein an acidic environment but insoluble in an alkaline or neutralenvironment. The HIV protease inhibitor nelfinavir mesylate is oneexample of such a drug. Portions of the drug that are undissolved cannotbe absorbed. Portions that are dissolved but not yet absorbed when theypass from the stomach into the small intestine may undergo precipitationand loss of their therapeutic benefit. This is confirmed by the factthat the presence of food in the GI tract substantially increases theabsorption of orally administered nelfinavir. Peak plasma concentrationand area under the plasma concentration-time curve of nelfinavir are twoto three times greater when doses are administered with or following ameal. This is believed to be due at least in part to enhanced retentionof the drug in the stomach.

SUMMARY OF THE INVENTION

[0051] The present invention resides in a controlled-release dosage formthat releases a drug at a rate that approaches zero-order, i.e., arelease rate that is substantially constant over time for a period ofseveral hours within the early part of the release profile of the drug,the dosage form substantially confining the release of the drug to theupper GI tract. The dosage form is a dual-matrix configuration, onematrix forming a core of polymeric material in which drug is dispersedand the other matrix forming a casing that surrounds and fully encasesthe core, the casing being of polymeric material that swells uponimbibition of water (and hence gastric fluid) to a size large enough topromote retention in the stomach during the fed mode, the shell and corebeing configured such that the drug contained in the core is releasedfrom the dosage form by diffusion through the shell. The shell is ofsufficient thickness and strength that it is not disrupted by theswelling and remains intact during substantially the entire period ofdrug release.

[0052] This dosage form offers benefits to each of the various types ofdrugs addressed above. For drugs such as amoxicillin, cefuroxime axetil,clindamycin, and others that tend to cause overgrowth of flora in thelower GI tract, the dosage form of this invention confines the deliveryof the drug to the stomach and upper small intestine in a slow,continuous manner. Drugs such as topiramate that are degraded by thegastric enzymes or by the low gastric pH are released more slowly andare protected from the degradation until they are released. Drugs suchas cyclosporine that are absorbed only at locations high in the GI tractand whose absorption varies widely among individuals benefit by thedosage form of this invention by being released with lesspatient-to-patient variability and by being retained in the regionswhere they are most effectively absorbed. Drugs such as doxifluridine,cyclosporine, and digoxin that are degradable by intestinal enzymes aredelivered with less degradation by concentrating their absorption in thestomach. Drugs that are influenced by inactivators such asp-glycoproteins in the lower GI tract are protected against suchinactivation by concentrating their release to the upper GI tract. Drugsthat are more bioavailable in an acidic environment are more effectivelyabsorbed by concentrating their release to the acidic environment of thestomach, and drugs that tend to lose solubility in an alkalineenvironment are enhanced by the acidic environment in the upper GItract. Other examples will be readily apparent to those knowledgeable inthe nature and characteristics of drugs.

[0053] While both the core and the shell may be water-swellable, thewater-swellability of the shell is a characteristic feature of thisinvention and extends to all embodiments of the invention. The polymericmaterial of the shell may be erodible as well as swellable, but when anerodible polymer is used, the polymer is one whose erosion rate issubstantially lower than the swelling rate. As a result, drug from thecore passes through the shell primarily by diffusion in preference torelease of the drug by erosion or dissolving of the shell. A furthercharacteristic feature of the invention that extends to all embodimentsis the inclusion of drug in the core, but a quantity of drug may also becontained in the shell or applied as a coating to the outside of theshell. This is useful in dosage forms that are designed to provide aninitial high rate of drug delivery of short duration or an initialimmediate release of the drug, followed by a slow continuous rate overan extended period of time. When drug is present in both the core andthe shell, the drug:polymer weight ratio in the shell is substantiallyless than the drug:polymer weight ratio in the core. This inventionfurther extends to dosage forms that contain a combination of two ormore drugs in a single dosage form, where either both drugs are presentthroughout the dosage form or one drug is dispersed in the core and theother in the shell.

[0054] These and other features, characteristics, and embodiments of theinvention will be apparent from the description that follows.

BRIEF DESCRIPTION OF THE DRAWING

[0055] The attached FIGURE is a plot of the excretion rate of metforminhydrochloride as a function of time from two dosage forms, one of whichis in accordance with this invention.

DETAILED DESCRIPTION OF THE INVENTION AND SPECIFIC EMBODIMENTS

[0056] Water-swellable polymers useful in the preparation of the dosageform of this invention include polymers that are non-toxic and, at leastin the case of the shell, polymers that swell in a dimensionallyunrestricted manner upon imbibition of water and hence of gastric fluid.The core polymer may also be a swelling polymer, and if so, compatiblepolymers will be selected that will swell together without disruptingthe integrity of the shell. The core and shell polymers may be the sameor different, and if the same, they may vary in molecular weight,crosslinking density, copolymer ratio, or any other parameter thataffects the swelling rate, so long as any swelling occurring in the corecauses substantially no splitting of the shell. Examples of suitablepolymers are:

[0057] cellulose polymers and their derivatives including, but notlimited to, hydroxymethyl cellulose, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropylmethyl cellulose,carboxymethylcellulose, and microcrystalline cellulose

[0058] polysaccharides and their derivatives

[0059] polyalkylene oxides

[0060] polyethylene glycols

[0061] chitosan

[0062] poly(vinyl alcohol)

[0063] xanthan gum

[0064] maleic anhydride copolymers

[0065] poly(vinyl pyrrolidone)

[0066] starch and starch-based polymers

[0067] maltodextrins

[0068] poly (2-ethyl-2-oxazoline)

[0069] poly(ethyleneimine)

[0070] polyurethane hydrogels

[0071] crosslinked polyacrylic acids and their derivatives

[0072] Further examples are copolymers of the polymers listed above,including block copolymers and graft polymers. Specific examples ofcopolymers are PLURONIC® and TECTONIC®, which are polyethyleneoxide-polypropylene oxide block copolymers available from BASFCorporation, Chemicals Div., Wyandotte, Mich., USA. Further examples arehydrolyzed starch polyacrylonitrile graft copolymers, commonly known as“Super Slurper” and available from Illinois Corn Growers Association,Bloomington Ill., USA.

[0073] The term “cellulose” is used herein to denote a linear polymer ofanhydroglucose. Preferred cellulosic polymers are alkyl-substitutedcellulosic polymers that ultimately dissolve in the GI tract in apredictably delayed manner. Preferred alkyl-substituted cellulosederivatives are those substituted with alkyl groups of 1 to 3 carbonatoms each. In terms of their viscosities, one class of preferredalkyl-substituted celluloses are those whose viscosities are within therange of about 3 to about 110,000 centipoise as a 2% aqueous solution at25° C. Another class are those whose viscosities are within the range ofabout 1,000 to about 5,000 centipoise as a 1% aqueous solution at 25° C.Particularly preferred alkyl-substituted celluloses are hydroxyethylcellulose and hydroxypropyl methylcellulose. Presently preferredhydroxyethyl celluloses are NATRASOL® 250HX and 250HHX NF (NationalFormulary), available from Aqualon Company, Wilmington, Del., USA.

[0074] Of the polyalkylene oxides that are useful in the dosage forms ofthis invention, particularly preferred examples are poly(ethylene oxide)and poly(propylene oxide). Poly(ethylene oxide) is a linear polymer ofunsubstituted ethylene oxide. Poly(ethylene oxide) polymers havingviscosity-average molecular weights of about 2,000,000 and higher arepreferred. More preferred are those with viscosity-average molecularweights within the range of about 2,000,000 to about 10,000,000, andeven more preferred are those with viscosity-average molecular weightswithin the range of about 4,000,000 to about 8,000,000. Poly(ethyleneoxide)s are often characterized by their viscosity in solution. Forpurposes of this invention, a preferred viscosity range is about 500 toabout 500,000 centipoise for a 2% aqueous solution at 25° C. Threepresently preferred poly(ethylene oxide)s are:

[0075] POLYOX® NF, grade WSR Coagulant, molecular weight 5 million

[0076] POLYOX® grade WSR 301, molecular weight 4 million

[0077] POLYOX® grade WSR 303, molecular weight 7 million

[0078] POLYOX® grade WSR N-60K, molecular weight 2 million

[0079] All four are products of Union Carbide Chemicals and PlasticsCompany Inc. of Danbury, Conn., USA. In certain embodiments of thisinvention, both the core matrix and the shell matrix are poly(ethyleneoxide), and the poly(ethylene oxide) used for the core has a highermolecular weight than the poly(ethylene oxide) used for the shell. Apreferred range of the viscosity-average molecular weight ratio(core:shell) is from about 1.15:1 to about 2.5:1. In another embodiment,the shell may have a higher molecular weight poly(ethylene oxide) thanthe core. For this embodiment the preferred range of theviscosity-average molecular weight ratio (core:shell) is from about0.2:1 to about 1:1.

[0080] Polysaccharide gums may be either natural and modified(semi-synthetic). Examples are dextran, xanthan gum, gellan gum, welangum and rhamsan gum. Xanthan gum is preferred. Alginates including, butnot limited to, sodium and calcium alginates may also be used.

[0081] Of the crosslinked polyacrylic acids, the preferred types arethose with a viscosity ranging from about 4,000 to about 40,000centipoise for a 0.5% aqueous solution at 25° C. Three presentlypreferred examples are CARBOPOL® NF grades 971P, 974P and 934P(BFGoodrich Co., Specialty Polymers and Chemicals Div., Cleveland, Ohio,USA). Further examples are polymers known as WATER LOCK®, which arestarch/acrylates/acrylamide copolymers available from Grain ProcessingCorporation, Muscatine, Iowa, USA.

[0082] The rate of release of drug from the core and the linearity ofthe amount released vs. time curve (i.e., the closeness of the releaseprofile to zero-order) will vary to some degree with the thickness ofthe shell. In most cases, best results will be achieved with a shellhaving a thickness that is at least about 0.5% of the longest lineardimension of the dosage form. In preferred embodiments, the shellthickness is from about 1% to about 60% of the longest linear dimensionof the dosage form. In further preferred embodiments, the shellthickness is from about 1.5% to about 45% of the longest lineardimension, and in the most preferred embodiments, the shell thickness isfrom about 2% to about 30% of the longest linear dimension.

[0083] The drug that is contained in the dosage form for controlledrelease may be any chemical compound, complex or composition that issuitable for oral administration and that has a beneficial biologicaleffect, preferably a therapeutic effect in the treatment of a disease oran abnormal physiological condition. Examples of high solubility drugsto which this invention is applicable are metformin hydrochloride,vancomycin hydrochloride, captopril, lisinopril, erythromycinlactobionate, ranitidine hydrochloride, sertraline hydrochloride,ticlopidine hydrochloride, baclofen, amoxicillin, cefuroxime axetil,cefaclor, clindamycin, levodopa, doxifluridine, thiamphenicol, tramadol,fluoxitine hydrochloride, ciprofloxacin, bupropion, and esters ofampicillin. Examples low solubility drugs to which this invention isapplicable are saguinavir, ritonavir, nelfinavir, clarithromycin,azithromycin, ceftazidime, acyclovir, ganciclovir, cyclosporin, digoxin,paclitaxel, iron salts, topiramate, and ketoconazole. Other drugssuitable for use and meeting the solubility criteria described abovewill be apparent to those skilled in the art.

[0084] Drugs suitable for delivery by the dosage forms of this inventioninclude drugs of low solubility in aqueous media, drugs of moderatesolubility, and drugs of high solubility. This invention is ofparticular interest for drugs whose solubility in water is greater thanone part by weight of drug in 25 parts by weight of water. Thisinvention is of further interest for drugs of solubility greater thanone part by weight of drug per five parts by weight of water.

[0085] The invention is also of use with drugs that have been formulatedto include additives that impart a small degree of hydrophobic characterto further retard the release rate of the drug into the gastric fluid.One example of such a release rate retardant is glyceryl monostearate.Other examples are fatty acids and salts of fatty acids, one example ofwhich is sodium myristate. The quantities of these additives whenpresent can vary; and in most cases, the weight ratio of additive todrug will range from about 1:20 to about 1: 1, and preferably from about1:8 to about 1:2.

[0086] In preferred embodiments of the invention, the drug will bepresent only in the core of the dosage form and not in the shell. Inother embodiments, however, a small amount of the drug will also bepresent in the shell as a means of releasing an initial amount of thedrug at a relatively high rate from the dosage form, before the slowcontinuous release of drug from the core. In general, the drug:polymerweight ratio in the shell is equal to or less than about 0.5 times thedrug:polymer weight ratio in the core. In more preferred embodiments,the drug:polymer weight ratio in the shell is equal to or less thanabout 0.25 times the drug:polymer weight ratio in the core, and in themost preferred embodiments, the drug:polymer weight ratio in the shellis equal to or less than about 0.05 times the drug:polymer weight ratioin the core.

[0087] In some embodiments of this invention, particularly those inwhich the drug is highly soluble in gastric fluid, the dosage formcontains an additional amount of the drug applied as a quicklydissolving coating on the outer surface of the dosage form. This coatingis referred to as a “loading dose” and its purpose is to provide, uponingestion of the dosage form and without first diffusing through apolymer matrix, immediate release into the patient's bloodstream. Anoptimal “loading dose” is one that is high enough to quickly raise theblood concentration of the drug but not high enough to produce thetransient overdosing that is characteristic of highly soluble drugs thatare not formulated in accordance with this invention. When a loadingdose coating is present, the preferred amounts of drug in the coatingrelative to the core are those listed in the preceding paragraph withthe coating considered as part of the shell.

[0088] A film coating may also be included on the outer surface of thedosage form for reasons other than a loading dose. The coating may thusserve an aesthetic function or a protective function, or it may make thedosage form easier to swallow or to mask the taste of the drug.

[0089] Turning to the core itself, the weight ratio of drug to polymerin the core may vary. Optimal ratios will depend on the drug solubility,the therapeutic dose, the desired release rate, the polymer and itsmolecular weight, and the types and amounts of any excipients that maybe present in the formulation. The drug:polymer ratio will generally beselected such that at least about 40% of the drug initially in the coreremains unreleased one hour after immersion of the dosage form ingastric fluid and substantially all of the drug has been released withinabout 24 hours after immersion. In preferred embodiments, the ratio willbe selected such that at least about 40% of the drug initially in thecore remains unreleased two hours after immersion has begun, or morepreferably such that at least about 60% of the drug initially in thecore remains unreleased two hours after immersion, and most preferablysuch that at least about 70% of the drug initially in the core remainsunreleased two hours after immersion.

[0090] The drug loading may also be characterized in terms of the weightpercent of drug in the core. In preferred embodiments, the drugconstitutes from about 1% to about 98% by weight of the core. In morepreferred embodiments, the drug constitutes from about 5% to about 95%by weight of the core, and in the most preferred embodiments, the drugconstitutes from about 50% to about 93% by weight of the core.

[0091] The dosage forms of this invention may assume a variety of forms,shapes and sizes, provided that the shell upon imbibing gastric fluidswells to a size that promotes the retention of the dosage form in theupper GI tract. Preferred dosage forms are tablets and capsules. Tabletsin accordance with this invention consist of an inner continuous solidcore which may be porous but is a coherent mass for at least a portionof the time that the tablet is in contact with gastric fluid, surroundedby a continuous solid shell whose inner surface is in full contact withthe outer surface of the core and which has the attributes of the shellof this invention as described above. Capsules in accordance with thisinvention consist of a core made up of one or more particles or tablets(of uniform or single-matrix construction) loosely retained in anunconnected enclosure which serves as the shell and has the attributesof the shell of this invention as described above. A shell may also beconstructed by first forming a polymer film and then sealing the filmaround the core, possibly by heat shrinking. Still further methodsinclude overcoating or dipping of the core in a shell-forming solutionor suspension.

[0092] Tablets that include a shell as part of the tablet, i.e., a shellthat is in full contact with the outer surface of the core, arepreferred, and can be prepared by a two-stage tabletting method. Thefirst stage is the preparation of the core, which can be achieved byconventional techniques, such as mixing, comminution, and fabricationtechniques readily apparent to those skilled in the manufacture of drugformulations. Examples of such techniques are:

[0093] (1) Direct compression using appropriate punches and dies, suchas those available from Elizabeth Carbide Die Company, Inc., McKeesport,Pa., USA. The punches and dies are fitted to a suitable rotarytabletting press, such as the Elizabeth-Hata single-sided Hata AutoPress machine, with either 15, 18 or 22 stations, and available fromElizabeth-Hata International, Inc., North Huntington, Pa., USA.;

[0094] (2) Injection or compression molding using suitable molds fittedto a compression unit, such as those available from Cincinnati Milacron,Plastics Machinery Division, Batavia, Ohio, USA.;

[0095] (3) Granulation such as, but not limited to, fluid bed or highshear granulation or roller compaction, followed by compression; and

[0096] (4) Extrusion of a paste into a mold or to an extrudate to be cutinto lengths.

[0097] The second stage of the preparation is the formation of theshell. This can be accomplished by any of steps (1), (2), or (3)performed directly over the core. Advanced tablet presses are availablethat include pick-and-place functions that are readily adaptable toperforming the sequential operations needed to form both the core andthe shell.

[0098] When particles are made by direct compression, the addition oflubricants may be helpful and is sometimes important to promote powderflow and to prevent capping of the particle (the breaking off of aportion of the particle) when the pressure is relieved. Usefullubricants are magnesium stearate (in a concentration of from 0.25% to3% by weight, preferably about 1% or less by weight, in the powder mix),and hydrogenated vegetable oil (preferably hydrogenated and refinedtriglycerides of stearic and palmitic acids at about 1% to 5% by weight,most preferably about 2% by weight). Additional excipients may be addedto enhance powder flowability, tablet hardness, and tablet friabilityand to reduce adherence to the die wall.

[0099] As indicated above, the dosage forms of the present inventionfind their greatest utility when administered to a subject who is in thedigestive state, which is also referred to as the postprandial or “fed”mode. The postprandial and interdigestive (or “fasting”) modes aredistinguishable by their distinct patterns of gastroduodenal motoractivity which determine the gastric retention or gastric transit timeof the stomach contents.

[0100] In the interdigestive mode, the fasted stomach exhibits a cyclicactivity called the interdigestive migrating motor complex (IMMC). Thecyclic activity occurs in four phases:

[0101] Phase I is the most quiescent, lasts 45 to 60 minutes, anddevelops few or no contractions.

[0102] Phase II is marked by the incidence of irregular intermittentsweeping contractions that gradually increase in magnitude.

[0103] Phase III, which lasts 5 to 15 minutes, is marked by theappearance of intense bursts of peristaltic waves involving both thestomach and the small bowel.

[0104] Phase IV is a transition period of decreasing activity whichlasts until the next cycle begins.

[0105] The total cycle time of the interdigestive mode is approximately90 minutes and thus, powerful peristaltic waves sweep out the contentsof the stomach every 90 minutes. The IMMC may function as an intestinalhousekeeper, sweeping swallowed saliva, gastric secretions, and debristo the small intestine and colon, preparing the upper tract for the nextmeal while preventing bacterial overgrowth. Pancreatic exocrinesecretion of pancreatic peptide and motilin also cycle in synchrony withthese motor patterns.

[0106] The postprandial or fed mode is normally induced by foodingestion, and begins with a rapid and profound change in the motorpattern of the upper GI tract, the change occurring over a period of 30seconds to one minute. The stomach generates 3-4 continuous and regularcontractions per minute, similar to those of the interdigestive mode butof about half the amplitude. The change occurs almost simultaneously atall sites of the GI tract, before the stomach contents have reached thedistal small intestine. Liquids and small particles flow continuouslyfrom the stomach into the intestine. Contractions of the stomach resultin a sieving process that allows liquids and small particles to passthrough a partially open pylorus. Indigestible particles greater thanthe size of the pylorus are retropelled and retained in the stomach.Particles exceeding about 1 cm in size are thus retained in the stomachfor approximately 4 to 6 hours. The dosage form of the present inventionis designed to achieve the minimal size through swelling followingingestion during the fed mode.

[0107] The postprandial or fed mode can also be inducedpharmacologically, by the administration of pharmacological agents thathave an effect that is the same or similar to that of a meal. Thesefed-mode inducing agents may be administered separately or they may beincluded in the dosage form as an ingredient dispersed in the shell, inboth the shell and the core, or in an outer immediate release coating.Examples of pharmacological fed-mode inducing agents are disclosed inco-pending U.S. patent application Ser. No. 09/432,881, filed Nov. 2,1999, entitled “Pharmacological Inducement of the Fed Mode for EnhancedDrug Administration to the Stomach,” inventors Markey, Shell, andBerner, the contents of which are incorporated herein by reference.

[0108] The following examples are offered by way of illustration ratherthan limitation.

EXAMPLE 1 Compressed Core-and-Shell Tablets of Metformin Hydrochloride

[0109] This example illustrates the preparation and release ratebehavior of a tablet in accordance with the invention, with a 600-mgcore and a 200-mg shell, both of poly(ethylene oxide) and additionallycontaining metformin hydrochloride in the core only, in a quantityamounting to 62.5% by weight of the core. The term “compressedcore-and-shell tablet” is used herein to denote a tablet formed by firstcompressing the core in a tablet press from a powdered mixture and thenusing a suitable tablet press to compress another powdered mixture overthe core to form the shell. This is distinct from methods of forming acapsule.

[0110] To prepare the core, a powder blend was prepared by mixingtogether metformin hydrochloride (9.374 parts by weight), POLYOX 301(molecular weight approximately 4,000,000, 5.478 parts by weight), andmagnesium stearate (0.151 parts by weight). A 600-mg portion of themixture was placed on a Carver Auto C Press and compressed at 2500 lbpressure (11,100 Newtons) with a zero-second dwell time and pump speedset at 100%, using a modified capsule die set measuring 0.274×0.725 inch(0.70×1.84 cm), to form the core. The core thus formed was placed in atablet die measuring 0.375×0.75 inch (0.95×1.90 cm), and surrounded byPOLYOX 303 powder (molecular weight approximately 7,000,000) withbetween 60 and 68 mg of POLYOX 303 underneath the core and 134 to 137 mgof POLYOX 303 on the sides and on top of the core, for a total shellweight of approximately 200 mg. The core and surrounding polymer werethen pressed at 2500 lb pressure (11,100 Newtons).

[0111] To estimate the release rate of the resulting shell-encasedtablets into gastric fluid, the tablets were placed in modifiedsimulated gastric fluid at pH 1.2 at 37° C., and the release of themetformin into the acid was measured as a function of time using amodified USP Type II (paddle with cones) Dissolution Apparatus rotatingat 60 rpm. Metformin released into the solution was detected byreverse-phase HPLC. The amounts released at intervals of 2, 4, 6, and 8hours are listed in Table I below and demonstrate a release rate thatapproaches zero order. TABLE I Metformin Hydrochloride Release StudyAmount Released Time from Start of Test (Percentage of (hours) Total inCore) 2 20.6 4 41.7 6 58.5 8 70.7

EXAMPLE 2 Compressed Core-and-Shell Tablets of Metformin Hydrochloride

[0112] This example is a further illustration of the preparation andrelease rate characteristics of a metformin hydrochloride tablet inaccordance with the invention. The procedure of Example 1 was repeated,using nearly identical quantities of materials, except that thepoly(ethylene oxide) used as the core matrix was POLYOX Coagulant(molecular weight approximately 5,000,000) rather than POLYOX 301(molecular weight approximately 4,000,000). The release rate results arelisted in Table II, which shows that the release rate again approachedzero order. TABLE II Metformin Hydrochloride Release Study AmountReleased Time from Start of Test (Percentage of (hours) Total in Core) 217.3 4 37.4 6 55.3 8 69.5

EXAMPLE 3 Compressed Core-and-Shell Tablets of Metformin Hydrochloride

[0113] This example is a further illustration of the preparation andrelease rate characteristics of a metformin hydrochloride tablet inaccordance with the invention, similar to that of Examples 1 and 2. Inthis example, however, metformin hydrochloride constituted 83.3% byweight of the core (and present only in the core, as in Examples 1 and2), and the higher molecular weight poly(ethylene oxide) (POLYOX 303)was used for the core while the lower molecular weight poly(ethyleneoxide) (POLYOX 301) was used for the shell. Otherwise, the procedureswere essentially the same as those of Examples 1 and 2, except that thedie for the outer shell measured 0.3125×0.75 inch (0.79×1.90 cm). Theresults are listed in Table III, which shows that the release rate againapproached zero order. TABLE III Metformin Hydrochloride Release StudyAmount Released Time from Start of Test (Percentage of (hours) Total inCore) 2 21.5 4 45.6 6 65.4 8 78.2

EXAMPLE 4 Compressed Core-and-Shell Tablets of Metformin Hydrochloride

[0114] This example is a further illustration of the preparation andrelease rate characteristics of a metformin hydrochloride tablet inaccordance with the invention, the tablet in this case being larger thanthose of the preceding examples, with a 700 mg core and a 300 mg shell.The drug was 71.3% by weight (present in the core only), and polymermatrices were the same as those of Example 3. The dies in the tablettingpress measured 0,274×0.725 inch (0.70×1.84 cm) for the core and0.375×0.75 inch (0.95×1.90 cm) for the shell.

[0115] The results are listed in Table IV, which shows that the releaserate again approached zero order. TABLE IV Metformin HydrochlorideRelease Study Amount Released Time from Start of Test (Percentage of(hours) Total in Core) 2 13.2 4 31.2 6 48.3 8 61.5

EXAMPLE 5 Compressed Core-and-Shell Tablets of Metformin Hydrochloride

[0116] A further metformin hydrochloride tablet may be prepared inaccordance with the invention with a 600 mg core of hydroxypropylcellulose and a 200-mg shell of poly(ethylene oxide), using a diemeasuring 0.3125×0.75 inch (0.79×1.90 cm). The metformin hydrochloride(residing only in the core) will amount to 83.3% by weight of the core.The hydroxypropyl cellulose in this example is KLUCEL® HPC HF.

EXAMPLE 6 Core-Coated Tablets of Metformin Hydrochloride

[0117] This example illustrates the preparation and release ratecharacteristics of a metformin hydrochloride tablet using the samematerials as Example 5, except with a 700 mg core and a 300 mg shell,and a drug loading (in the core only) of 71.4% by weight. The resultsare listed in Table VI, which shows that the release rate againapproached zero order. TABLE VI Metformin Hydrochloride Release StudyAmount Released Time from Start of Test (Percentage of (hours) Total inCore) 2 35.5 4 61.3 6 76.0 8 84.4

EXAMPLE 7 Compressed Core-and-Shell Tablets of Metformin Hydrochloride(Ref. NB 36, pp. 31; NB 34, pp. 92-95)

[0118] This example illustrates the preparation and release ratecharacteristics of a metformin hydrochloride tablet similar to those ofthe preceding examples, except that the shell was constructed of amixture of poly(ethylene oxide) (of low molecular weight relative to thesame polymer in the core) and EUDRAGIT® L100-55 methacrylic polymers(Röhm America, Inc., Piscataway, N.J. USA). The weight ratio ofpoly(ethylene oxide) to methacrylic polymer in the shell was 1.48:1, thepoly(ethylene oxide) in the core was POLYOX 303 (molecular weight7,000,000) and the poly(ethylene oxide) in the shell was POLYOX 301(molecular weight 4,000,000). The drug was present in the core only, at83.3% by weight of the core. The results are listed in Table VII, whichshows that the release rate again approached zero order. TABLE VIIMetformin Hydrochloride Release Study Amount Released Time from Start ofTest (Percentage of (hours) Total in Core) 2 30.7 4 56.6 6 74.4 8 84.1

EXAMPLE 8 Compressed Core-and-Shell Tablets of Metformin Hydrochloride

[0119] This example illustrates the preparation and release ratecharacteristics of metformin hydrocholoride tablets similar to those ofthe preceding examples, except that three different polymers blends wereused to form the shells of the tablets:

[0120] Shell A Polymer: POLYOX 301

[0121] Shell B Polymer: blend of POLYOX 301 and EUDRAGIT L100-55,POLYOX:EUDRAGIT weight ratio 3.9:1

[0122] Shell C Polymer: blend of POLYOX 301 and KOLLIDON 90F(polyvinylpyrrolidone, BASF AG, Ludwigshafen, Germany), POLYOX:KOLLIDONweight ratio 3.9:1

[0123] The core each case was 600 mg and the shell was 200 mg, and thedrug (present only in the core ) constituted 83.3% by weight of thecore. The results are listed In Table VIII, which shows that the releaserate approached zero order at early times before the driving wasdepleted. TABLE VIII Metformin Hydrochloride Release Study AmountReleased Time from Start of Test (Percentage of Total in Core) (hours)Shell A Shell B Shell C 1 15.1 11.3 15.7 2 34.0 29.3 38.9 3 55.3 45.354.3 4 82.8 54.5 60.1 6 93.1 61.7 63.8

EXAMPLE 9 Compressed Core-and-shell Tablets of Metformin Hydrochloride

[0124] This example illustrates the preparation and release ratecharacteristics of a metformin hydrochloride tablet similar to those ofthe preceding examples, except with a lower proportion of the shell tocore. In particular, the core was 700 mg and the shell was 200 mg. Thedrug loading in the core was 71.4% by weight (with no drug contained inthe shell). the core polymer matrix was POLYOX 303, and the shellpolymer matrix was POLYOX 301. The results are listed in Table IX, whichshows that the release rate approached zero order. TABLE IX MetforminHydrochloride Release Study Amount Released Time from Start of Test(Percentage of (hours) Total in Core) 2 20.3 4 40.2 6 56.7 8 70.8

EXAMPLE 10 Compressed Core-and-Shell Tablets of Metformin Hydrochloride

[0125] This example illustrates the preparation and release ratecharacteristics of metforming hydrocholoride tablets similar to those ofthe EXAMPLE 9, except using poly(ethylene oxide) of the molecular weightin both the core and the shell. The core in these tablets was 800 mg insize, the shell was 250 mg in size, and the drug loading in the core was79.2% by weight (with no drug in the shell). The results are listed inTable X, which shows that the release rate approached zero order. TABLEX Metformin Hydrochloride Release Study Amount Released Time from Startof Test (Percentage of (hours) Total in Core) 2 15.9 4 34.6 6 50.2 863.9

EXAMPLE 11 Compressed Core-and-Shell Tablets of Metformin HydrochlorideWith Various Polymers

[0126] This example demonstrates the release rates of metforminhydrochloride tablets in accordance with this invention, using variouscombinations of polymers for the core and shell. In each case, the coreand shell were 600 mg and 200 mg in weight, respectively, eachcontaining 1.0% by weight magnesium stearate, and the drug loading inthe core was 83.3% by weight (and no drug in the shell). The apparatusused for measuring the release rate was a USP Type I (10-mesh baskets)Dissolution Apparatus rotating at 100 rpm with 900 mL of modifiedsimulated gastric fluid (at pH 1.2), and the amount of drug released wasdetected by reverse-phase HPLC. The various polymers used were asfollows (all molecular weights are viscosity average molecular weightsand are approximate):

[0127] POLYOX® 301—poly(ethylene oxide), molecular weight 4,000,000,Union Carbide Corporation, Danbury, Conn., USA

[0128] POLYOX® 303—poly(ethylene oxide), molecular weight 7,000,000,Union Carbide Corporation, Danbury, Conn., USA

[0129] POLYOX® Coagulant—poly(ethylene oxide), molecular weight5,000,000, Union Carbide Corporation, Danbury, Conn., USA

[0130] NATROSOL® 250 HHX Pharm—hydroxyethyl cellulose, Brookfieldviscosity of 1% solution at 25° C.: 3,500-5,500 cps, Hercules,Incorporated, Aqualon Division, Wilmington, Del. USA

[0131] KLUCEL® HXF—hydroxypropyl cellulose, Brookfield viscosity of 1%solution at 25° C.: 1,500-3,000 cps, Hercules, Incorporated, AqualonDivision, Wilmington, Del. USA

[0132] The release rate results are shown in Table XI. TABLE XIMetformin Hydrochloride Release Study Amount of Drug Released(Percentage of Total in Core) Core Polymer Shell Polymer 2 h 4 h 6 h 8 hPOLYOX 301 POLYOX 303 30 65 87 96 POLYOX Coagulant POLYOX 301 29 63 8697 NATROSOL NATROSOL 39 68 86 95 250 HHX 250 HHX KLUCEL HXF NATROSOL 2956 74 86 250 HHX

EXAMPLE 12 Capsules of Metformin Hydrochloride

[0133] This example illustrates the preparation and release ratecharacteristics of a cylindrical capsule in which the capsule shellserves as the shell of the invention, loosely surrounding a compressedtablet that serves as the core containing the drug. The drug used inthis preparation was metformin hydrochloride.

[0134] The tablet was prepared by blending 3.329 parts by weight ofmetformin hydrochloride, 0.630 parts by weight of POLYOX 303 and 0.039parts by weight of magnesium stearate to from a 400-mg core. The blendwas pressed into tablet form on a Carver Auto C Press at 1500 lbpressure (6,670 Newtons) with a zero-second dwell time and 100% pumpspeed using a 15.35×5.6 mm die. To prepare the capsule, POLYOX 301 wasmelted between two glass plates that had been previously sprayed withmold release (Dry Film PTFE, McMaster-Carr). The dry poly(ethyleneoxide) film that was thus formed was cut into rectangles and wrappedaround TEFLON® bars to form a 0.25 inch (0.64 cm) diameter cylinder. Oneend of each cylinder was melt-sealed between two glass plates in a 100°C. oven. One tablet was placed inside each cylinder, and the unsealedend of the cylinder was then melt-sealed. Another set of capsules wasprepared by wrapping each tablet in a sheet of the POLYOX 301 film(prepared between glass plates as described above) and pinching the endsof the wrapped film to close the capsule.

[0135] The release of the drug from the wrapped capsules (the second setdescribed in the preceding paragraph) into modified simulated gastricfluid at 37° C. was measured as a function of time using an USP Type I(10 mesh baskets) Dissolution Apparatus rotating at 100 rpm. The drugwas detected by reverse phase HPLC at 2, 4, 6, and 8 hours. The resultsare listed the Table XII below, showing a release rate that approacheszero order. TABLE XII Metformin Hydrochloride Release Study AmountReleased Time from Start of Test (Percentage of (hours) Total in Core) 2 0.8 4 11.7 6 32.9 8 59.1

EXAMPLE 13 Compressed Core-and-Shell Tablets of Riboflavin-5′-Phosphate

[0136] This example illustrates the preparation and release ratecharacteristics of a tablet in accordance with invention, in which thedrug is riboflavin-5′-phosphate (present only in the core). The core wasprepared by compression tabletting and the shell was formed around thecore in the same manner, both as described above in Examples 1 through11. The core in this tablet was 700 mg in weight, the shell was 200 mgin weight, and the drug loading in the core was 11.1% by weight. Inaddition to the drug, the core formulation contained 60.3% by weight oflactose monohydrate, 27.6% POLYOX 303, and 1.0% magnesium stearate. Theshell was POLYOX 301 with 1.0% magnesium stearate. The detection ofreleased riboflavin-5′-phosphate was accomplished by UV spectroscopy.

[0137] The release rate results are listed in Table XIII, which shows arelease profile that is faster than zero order. TABLE XIIIRiboflavin-5′-Phosphate Release Study Amount Released Time from Start ofTest (Percentage of Total (hours) in COre) 2 1.3 4 2.7 6 4.8 8 8.0

EXAMPLE 14 Compressed Core-and-Shell Tablets of Aspirin

[0138] This example illustrates the preparation and release ratecharacteristics of a tablet in accordance with the invention by theprocedures of Examples 1-11 above, in which the drug is aspirin (presentonly in the core). The core in this tablet was 400 mg in weight, theshell was 200 mg in weight, and the aspirin loading was 81.3% by weightof the core. In addition to the aspirin, the core formulation contained17.7% POLYOX 303, and 1.0% magnesium stearate. The shell was 39.268%POLYOX 301 and 59.667% EUDRAGIT L110-55 with 1.065% magnesium stearate.

[0139] Release rate data were determined by release into 900 mL ofacetate buffer at pH 4.5, as specified in the USP method forimmediate-release aspirin, and a USP Type I Dissolution Apparatus wasused. The released aspirin was detected by reverse-phase HPLC. Theresults are listed in Table XIV, showing a release rate that approacheszero order. TABLE XIV Aspirin Release Study Amount Released Time fromStart of Test (Percentage of Total (hours) in Core) 1.5 0.90 3 2.62 4.54.57 6 6.75

EXAMPLE 15 In Vivo Comparison Study

[0140] This example presents a comparison between the release ratecharacteristics of a compressed core-and-shell tablet of the presentinvention in which the drug is present only in the core and animmediate-release formulation of the same drug. The drug in each casewas metformin hydrochloride, and the two tablets were as follows:

[0141] Tablet A: Core: 600 mg, of which 78.33% by weight was metforminhydrochloride, 15.67% by weight was POLYOX 303, 5% miscellaneousexcipients present in GLUCOPHAGE® (Bristol-Myers Squibb), and 1% byweight was magnesium stearate Shell: 200 mg, of which 99% by weight wasPOLYOX 301 and 1% by weight was magnesium stearate

[0142] Tablet B: GLUCOPHAGE®, Bristol-Myers Squibb, containing 500 mgmetformin hydrochloride with 6% miscellaneous excipients

[0143] Three healthy adult human subjects were each administered one ofeach of the tablets with 100 mL water in the morning immediately after astandard specified breakfast. A standard specified lunch was taken byeach subject. Water was drunk by each subject at a rate of 60 mL perhour. Vital signs (blood pressure and heart rate) and blood samples forglucose measurements were taken prior to dosing, and at 2, 4, and 8hours after dosing on the first day.

[0144] All urine voids were collected from each subject for 72 hoursafter dosing, following emptying of the bladder prior to dosing. Urinecollections were made immediately prior to dosing and at accumulated0-1, 1-2, 2-4, 4-6, 6-8, 8-10, and 10-12 hours after dosing. Subsequenturine collections were accumulated over 12-hour periods for the next twodays. The urine samples were then analyzed for metformin hydrochlorideby an HPLC method adapted from that described in Caillé, G., Biopharm.Drug Dispos. 14 (1993): 257-263. The results, expressed in terms of theexcretion rate of metformin hydrochloride in mg/h vs. time after dosage(in hours), are shown in FIG. 1, where the triangle-shaped points arethe data from Tablet A (representing the present invention) and thediamond-shaped points are the data from Tablet B. The Tablet A curvedemonstrates,a clear advantage over the Tablet B curve by virtue of thelower slope and essentially linear shape of the Tablet A curve upthrough five hours (with continued delivery through 7 hours). Byavoiding an initial burst of metformin, the present invention lessensthe occurrence of gastrointestinal and taste disturbances.

[0145] The foregoing is offered primarily for purposes of illustration.It will be readily apparent to those skilled in the art that thecomponents, additives, proportions, methods of formulation, and otherparameters of the invention can be modified further or substituted invarious ways without departing from the spirit and scope of theinvention.

What is claimed is:
 1. A controlled-release oral drug dosage form forreleasing a drug into at least a portion of a region defined by thestomach and the upper gastrointestinal tract, said dosage formcomprising: (a) a core comprising a first solid polymeric matrix withsaid drug dispersed therein, and (b) a shell substantially completelyencasing said core, said shell comprising a second solid polymericmatrix that swells upon imbibition of water to a size large enough topromote retention in the stomach while the stomach is in a fed mode, andsaid shell having a drug:polymer weight ratio that is substantially lessthan that of said core, said shell having a thickness that is at leastabout 0.5% of the longest linear dimension of said dosage form, saidsecond polymeric matrix being of a material and thickness relative tosaid core such that when said dosage form is immersed in gastric fluid,said drug is released from said dosage form into said gastric fluid at acontrolled rate limited at least in part by diffusion of said drugthrough said shell to an extent that at least about 40% of said drugremains unreleased one hour after such immersion has begun andsubstantially all of said drug is released within about twenty-fourhours after such immersion has begun.
 2. A controlled-release oral drugdosage form in accordance with claim 1 in which said core has an outersurface and said shell has an inner surface in full contact with saidouter surface of said core.
 3. A controlled-release oral drug dosageform in accordance with claim 1 in which said shell thickness is fromabout 1% to about 60% of the longest linear dimension of said dosageform.
 4. A controlled-release oral drug dosage form in accordance withclaim 1 in which said shell thickness is from about 1.5% to about 45% ofthe longest linear dimension of said dosage form.
 5. Acontrolled-release oral drug dosage form in accordance with claim 1 inwhich said shell thickness is from about 2% to about 30% of the longestlinear dimension of said dosage form.
 6. A controlled release oral drugdosage form in accordance with claim 1 in which the drug:polymer weightratio of said shell is equal to or less than about 0.5 times thedrug:polymer weight ratio of said core.
 7. A controlled release oraldrug dosage form in accordance with claim 1 in which the drug:polymerweight ratio of said shell is equal to or less than about 0.25 times thedrug:polymer weight ratio of said core.
 8. A controlled release oraldrug dosage form in accordance with claim 1 in which the drug:polymerweight ratio of said shell is equal to or less than about 0.05 times thedrug~polymer weight ratio of said core.
 9. A controlled release oraldrug dosage form in accordance with claim 1 in which said shell containssubstantially none of said drug.
 10. A controlled-release oral drugdosage form in accordance with claim 1 in which said oral drug dosageform is a tablet having a total weight of from about 50 mg to about 5000mg.
 11. A controlled-release oral drug dosage form in accordance withclaim 1 in which said oral drug dosage form is a tablet having a totalweight of from about 100 mg to about 3000 mg.
 12. A controlled-releaseoral drug dosage form in accordance with claim 1 in which said oral drugdosage form is a tablet having a total weight of from about 500 mg toabout 2000 mg.
 13. A controlled-release oral drug dosage form inaccordance with claim 1 in which said first and second polymericmatrices are formed of polymers independently selected from the groupconsisting of poly(ethylene oxide), poly(vinyl alcohol), cellulose,alkyl-substituted cellulose, hydroxyalkyl-substituted cellulose,crosslinked polyacrylic acids, and xanthan gum.
 14. A controlled-releaseoral drug dosage form in accordance with claim 1 in which said first andsecond polymeric matrices are formed of polymers independently selectedfrom the group consisting of poly(ethylene oxide), poly(vinyl alcohol),hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, and carboxymethyl cellulose.15. A controlled-release oral drug dosage form in accordance with claim1 in which said first and second polymeric matrices are formed ofpolymers independently selected from the group consisting ofpoly(ethylene oxide), hydroxypropylmethyl cellulose, and hydroxyethylcellulose.
 16. A controlled-release oral drug dosage form in accordancewith claim 1 in which said first and second polymeric matrices are bothpoly(ethylene oxide).
 17. A controlled-release oral drug dosage form inaccordance with claim 16 in which said poly(ethylene oxide) has amolecular weight of at least about 2,000,000.
 18. A controlled-releaseoral drug dosage form in accordance with claim 16 in which saidpoly(ethylene oxide) has a molecular weight of from about 2,000,000 toabout 10,000,000.
 19. A controlled-release oral drug dosage form inaccordance with claim 16 in which said poly(ethylene oxide) of saidfirst polymeric matrix has a higher molecular weight than saidpoly(ethylene oxide) of said second polymeric matrix.
 20. Acontrolled-release oral drug dosage form in accordance with claim 16 inwhich said poly(ethylene oxide) of said first polymeric matrix has alower molecular weight than said poly(ethylene oxide) of said secondpolymeric matrix.
 21. A controlled-release oral drug dosage form inaccordance with claim 19 in which the molecular weight ratio of saidpoly(ethylene oxide) of said first polymeric matrix to saidpoly(ethylene oxide) of said second polymeric matrix is from about1.15:1 to about 2.5:1.
 22. A controlled-release oral drug dosage form inaccordance with claim 1 in which the amount of said drug in said core isfrom about 1% to about 98% by weight.
 23. A controlled-release oral drugdosage form in accordance with claim 1 in which the amount of said drugin said core is from about 5% to about 95% by weight.
 24. Acontrolled-release oral drug dosage form in accordance with claim 1 inwhich the amount of said drug in said core is from about 50% to about93% by weight.
 25. A controlled-release oral drug dosage form inaccordance with claim 1 in which said second polymeric matrix is of amaterial and volume relative to said core that at least about 40% ofsaid drug remains unreleased two hours after such immersion has begun.26. A controlled-release oral drug dosage form in accordance with claim1 in which said second polymeric matrix is of a material and volumerelative to said core that at least about 60% of said drug remainsunreleased two hours after such immersion has begun.
 27. Acontrolled-release oral drug dosage form in accordance with claim 1 inwhich said second polymeric matrix is of a material and volume relativeto said core that at least about 70% of said drug remains unreleased twohours after such immersion has begun.
 28. A controlled-release oral drugdosage form in accordance with claim 1 in which said drug has asolubility in water of greater than one part by weight of said drug in25 parts by weight of water.
 29. A controlled-release oral drug dosageform in accordance with claim 1 in which said drug has a solubility inwater of greater than one part by weight of said drug in ten parts byweight of water.
 30. A controlled-release oral drug dosage form inaccordance with claim 1 in which said drug is a member selected from thegroup consisting of metformin hydrochloride, vancomycin hydrochloride,captopril, lisinopril, erythromycin lactobionate, acyclovir, ranitidinehydrochloride, baclofen, sertraline hydrochloride, levodopa, tramadol,and ticlopidine hydrochloride.
 31. A controlled-release oral drug dosageform in accordance with claim 1 in which said drug is a member selectedfrom the group consisting of amoxicillin, cefuroxime axetil, cefaclor,clindamycin, clarithromycin, azithromycin, ceftazidine, andciprofloxacin.
 32. A controlled-release oral drug dosage form inaccordance with claim 1 in which said drug is a member selected from thegroup consisting of cyclosporine, digoxin, doxifluridine, andpaclitaxel.
 33. A controlled-release oral drug dosage form in accordancewith claim 1 in which said drug is a member selected from the groupconsisting of esters of ampicillin, iron salts, digoxin, andketoconazole.
 34. A controlled-release oral drug dosage form inaccordance with claim 1 in which said drug is nelfinar mesylate.